PROJECT SUMMARY Breast cancer is one of the most common cancers in the US. Approximately 15% to 20% of cases exhibit a family history of the disease suggesting a strong heritable component. Susceptibility to breast cancer is associated with high-penetrance germline mutations in BRCA1, BRCA2, PTEN, STK11, CDH1, and TP53. In addition, inherited inactivating mutations in several other genes have been associated with familial breast cancer. These include ATM, CHEK2, PALB2, BRIP1, BARD1, RAD51C, RAD51D, XRCC2, NBN, RAD50, and MRE11A. While inactivating mutations in ATM and CHEK2 have been associated with moderate 3 to 7-fold increased risk of breast cancer with lifetime risks of between 20% and 50%, these risk estimates are imprecise and little is known about the risk of breast and other cancers associated with inactivating mutations in other predisposition genes. Clinical genetic testing for all of these high and moderate risk predisposition genes is now available. Many women, with personal and family history of breast, ovarian or other cancers, are pursuing testing for mutations with these panels, which has seen an upsurge in demand in response to `Angelina's story'. Initial data suggest that ~10% of panel tests identify truncating mutations and 20% yield variants of uncertain significance (VUS) in the form of missense and intronic changes of undefined clinical relevance in the known predisposition genes. Although potentially useful for establishing the etiology of breast cancer in a family, there remain significant limitations in the clinical interpretation of the results from the panel testing. In particular, the age-related risk of breast and other cancers associated with pathogenic mutations in the genes are largely undefined. Furthermore, clear age-related medical management recommendations have not been developed. Thus, the results of these tests can lead to confusion and uninformed medical decisions that can result in significant harm. Here we propose to establish the risks of breast and other cancers associated with pathogenic mutations and to classify the clinical relevance of VUS in known breast cancer predisposition genes using family based registry studies, along with functional and pathology studies as follows: Aim 1) Define the penetrance of cancers associated with inactivating mutations in panel-based predisposition genes; Aim 2) Determine the clinical relevance of VUS in panel-based known predisposition genes; Aim 3) Assess clinical- pathological features of mutations in cancer predisposition genes. At the conclusion of this population sciences-based study, improved risk assessment based on the risk estimates associated with pathogenic mutations in these genes, methods for establishing the clinical relevance of many VUS in the known predisposition genes, and data for establishing medical management recommendations for carriers of mutations in predisposition genes will be available.